This proposal is part of a long term project aiming to understand catalysis and ligand binding in enzymes. We have chosen for our studies the aspartic proteinase family, a group of enzymes that control a variety of important biological functions from protein turnover to the replication of the HIV virus. Our specific proposal offers a novel Ab-- initio method for the design of more effective and specific inhibitors, which in principle could have higher bio-availability, for the HIV-1 proteinase(HIV-1 PR), an enzyme involved in the formation of mature HIV-1 virions. The higher purported selectivity is based, in part, on the very different solvent-enzyme interactions present in the acidic/bacterial proteinases in one hand and the retroviral proteinases on the other, which the author found in the study on the sources for the active site acidity of these proteins. The putative inhibitor will be further improved by taking into account the generation of specific interactions that could be originated in the active site and specificity pockets of HIV-1 PR. The specific objectives of this research proposal are aimed at evaluating the actual affinity and specificity of the hypothetical inhibitors by the use of computer simulations. For this sake, the inhibitor-enzyme complexes will be built using the vast published information on the x-ray crystallography of related complexes. In parallel, the putative inhibitors will be synthesized in the Laboratory of Dr. M.Chorev(at the Hebrew University in Jerusalem) and its affinity and specificity will be tested in Dr. J. Tang's Laboratory( at Oklahoma Medical Center). The structural predictions for the complexes formed between the designed inhibitors with the HIV-1 PR and with some mammalian members of the aspartic proteinase family will be checked by X-ray crystallography performed by Dr. A. Wlodawer's group at NCI.